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Abstract  Two patients from different families have recently been described as having a deficiency of sterol-C4-methyl oxidase, encoded by the SC4MOL gene. Both patients presented with microcephaly, congenital cataracts, and growth delay in infancy. The first patient (a female), who is now 20 years old, has had severe, diffuse psoriasiform dermatitis everywhere except her palms since she was 6. The second patient, also female, is now 5 and has just started to develop dry skin and hair changes. Quantitative sterol analysis of both patients’ plasma showed marked elevation of 4α-methylsterols and 4,4′-dimethylsterols, indicating a deficiency in the first step of sterol-C4 demethylation in cholesterol biosynthesis.

Abstract  SC4MOL deficiency is the first autosomal recessive disorder identified in the sterol demethylation complex. Cellular studies with patient-derived fibroblasts have shown higher mitotic rates than control cells in cholesterol-depleted medium, with increased de novo cholesterol biosynthesis and accumulation of methylsterols. Immunologic analyses of granulocytes and B cells from patients and obligate carriers in the patients’ families indicated dysregulation of immune-related receptors. Inhibition of sterol-C4-methyl oxidase in human-transformed lymphoblasts induces activation of the cell cycle. These findings suggest that methylsterols influence mitotic capacity and immune function. SC4MOL is situated within the psoriasis susceptibility locus PSORS9 and may be a genetic risk factor for common psoriasis.

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